Inhibition of Rho-associated Protein Kinase for Treatment of Cerebral Cavernous Malformations
Abstract number :
3.145
Submission category :
2. Translational Research / 2E. Other
Year :
2022
Submission ID :
2204649
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Juan Gutierrez, MD – Neurelis, Inc.; Issam Awad, MD – Neurelis, Inc.; Leslie Morrison, MD – University of New Mexico Health Sciences Center; Helen Kim, MPH, PhD – University of California; Cenk Ayata, MD, PhD – Massachusetts General Hospital; Miguel Lopez-Toledano, PhD – Neurelis, Inc.; Sunita Misra, MD, PhD – Neurelis, Inc.; Adrian Rabinowicz, MD – Neurelis, Inc.; Enrique Carrazana, MD – Neurelis, Inc.; University of Hawaii John A. Burns School of Medicine
Rationale: Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system (CNS), and in the brain, they are associated with intracerebral bleeds and seizures. CCMs consist of a porous endothelial cell layer (loss of tight junctions) and lack healthy contractile cell types (pericytes, myocytes) and connective tissues. A rare vascular abnormality, CCMs occur in 0.4%-0.9% of the population. Seizures may occur as a product of microbleeds and/or disruption of the blood brain barrier, affecting neuronal homeostasis and excitation. Seizure is the second most common symptom of CCMs, with >25% of CCMs identified following an epilepsy diagnosis. Currently, surgical removal of the CCM can be considered for symptomatic lesions along with potential removal of epileptogenic tissue, while radiosurgery can be considered for lesions in eloquent areas. However, conservative approaches (antiseizure drugs) are preferred for single seizures. Surgical interventions are not recommended for asymptomatic lesions and may not be feasible for lesions in eloquent locations._x000D_
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The pathological signaling pathway is dynamic and can vary across different forms of CCM (familial, sporadic); however, several downstream effectors common to all CCMs represent potential therapeutic targets. One target, rho-associated protein kinase (ROCK), plays an integral role in the pathological (angiogenic) mechanism that leads to lesion development and growth, with the ROCK2 isoform predominant in the CNS.
Methods: A novel ROCK2 inhibitor, NRL-1049, was investigated to examine its effect on ROCK2 activity and CCM lesion volume and bleeding (McKerracher L, et al. Transl Stroke Res. 2020;11(3):365-376). A mouse model (C57BL/6) of transient middle cerebral artery occlusion (tMCAO) was used to assess the effect of NRL-1049 on ROCK2 activity. Lesion volume and bleeding were studied using heterozygous Ccm1+/− and Ccm3+/− knockout mice crossed with Msh2−/− and Trp53−/− backgrounds, respectively, which express lesions characteristic of human CCMs.
Results: NRL-1049 reduced levels of phosphorylated cofilin, a biomarker of ROCK2 activation, in brain tissue from tMCAO mice. Micro-computed tomography of whole brain from Ccm1+/−Msh2−/− and Ccm3+/−Trp53−/− mice revealed a reduction in lesion volume with NRL-1049 treatment as compared with placebo. The density of Perls Prussian blue staining, which detects non-heme iron, was less around lesions from Ccm3+/−Trp53−/− knockout mice treated with NRL-1049 than placebo, indicating that NRL-1049 is effective at reducing the degree of bleeding in this model.
Conclusions: Seizure is a common presenting symptom of CCM, and there is an unmet need for nonsurgical treatment options in patients with CCM. NRL-1049 is a selective ROCK2 inhibitor that has exhibited efficacy to reduce lesion burden in animal models of CCM, potentially through stabilization of the vascular endothelium. A clinical development program is being initiated to investigate further the potential of NRL-1049 as a treatment for CCM.
Funding: Neurelis, Inc.
Translational Research